Nutritionally complete liquid diet compositions have been increasingly employed over the past decade for nutritional support of undernourished patients or patients with gastrointestinal pathology. The term "elemental diet" as applied to these liquid diet compositions generally refers to an enterically administered liquid diet which provides the patient's basic nutritional requirements in an elemental, easily digestible source. The protein source in these diets is generally a protein hydrolysate or the individual amino acids in purified form or a mixture of these. Carbohydrates, the main caloric source ingredient in these diets, usually comprise sucrose and/or glucose or small polymers of glucose. The percentage of calories supplied as fat is usually limited, and in some diets the major portion of the administered fat is in the form of essential fatty acids. Vitamins, electrolytes and trace elements are also available in these elemental diets to meet nutritional requirements. These dietary compositions are typically marketed as dry blended or spray-dried powder that is reconstituted with water prior to consumption. The reconstituted liquid elemental diet is usually fed within two hours in most cases and generally should not be held for more than 24 hours, even when stored at refrigerated temperatures.
The general formulation and medical use of specialized liquid diets is not new. Crosby, et al, U.S. Pat. No. 3,256,095, granted June 14, 1966; disclosed a diet which could be administered either intravenously or orally for supplementation of patients with inadequate nutrition. The protein source for this particular diet was disclosed as being amides and/or acid salts of these amides of amino acids "indispensible" to the system of the mammal receiving the diet.
In U.S. Pat. No. 3,697,287, issued Oct. 10, 1972; Winitz disclosed a palatable aqueous emulsion (or dry aggregate, soluble in water) containing all essential amino acids, minerals, vitamins, carbohydrate, fat, and non-essential amino acids in balanced quantities to supply all nutritional needs for humans in such a form as to bypass normal digestive functions. For palatability, the maximum allowable levels of sulfur-containing amino acids and glutamate are specified. This diet formulation has the trade name Vivonex and is sold in commerce.
U.S. Pat. No. 3,698,912, granted Oct. 17, 1972 to Winitz covers the related process for treating a protein hydrolysate, involving removal of some components and addition of others, to give a palatable and nutritious balanced amino acid nutrient source which would be used as disclosed in accord with the '287 patent cited hereinabove.
In U.S. Pat. No. 3,701,666, also granted to Winitz on Oct. 31, 1972, a related process is disclosed for making palatable compositions composed entirely of purified individual amino acids, carbohydrates, fats, vitamins, and salts. This patent further specifies that the diet can be formulated as a solid, a concentrate, or as an immediate-use canned product following pasteurization of the liquid emulsion.
An additional patent to Winitz, U.S. Pat. No. 3,849,554, granted Nov. 19, 1974, discloses a method for lowering blood serum cholesterol by restricting subjects to a defined diet composition consisting essentially of vitamins, minerals, amino acids, essential fatty acids and a carbohydrate component selected from glucose, maltose and/or polysaccharides of glucose.
Of less relevance are the following patent disclosures. U.S. Pat. No. 3,773,930, issued Nov. 20, 1973 to K. Mohammed, et al, addresses improvement of flavor in low residue dietaries which are composed of amino acids, starches and/or sugars, minor amounts of fat, vitamins and minerals; by incorporating pectin and various fruit flavorings.
Snell in U.S. Pat. No. 3,793,450, issued Feb. 19, 1974 discloses stable dietary compositions for intravenous infusion, such compositions containing 1-10% of amino acids as free bases in a 1-15% fat emulsion, such as soya bean oil, this emulsion being stabilized with either soya or egg yolk phosphatides.
Fisher, et al., in U.S. Pat. No. 3,950,529, granted Apr. 13, 1976, discloses liquid diets formulated for intravenous or oral administration to patients with liver disease. These diets comprise a sterilized solution of amino acids in specified novel relative proportions, e.g. (isoleucine+leucine+valine) being 40-300 times tryptophane and approximately 15-135 times (phenylalanine or phenylalanine+tyrosine) for intravenous administration. For oral administration, this amino acid mixture is mixed with carbohydrates and/or fat, vitamins and minerals and reconstituted with water. This liquid diet is not subjected to sterilization but is made up prior to usage.
Although improvements in these compositions have evolved with the increasing widespread use of the diets in nutritional management of patients, some problems have persisted. While liquid diet compositions in immediate-use form have been previously disclosed (see the Winitz patents described hereinabove); no diet in this form has been made available on a commercial scale. This is in spite of the convenience offered by an elemental diet in a ready-to-use form. Considerable economies in hospital or institutional use could be realized as commissary space, equipment, and labor involved in reconstituting current powder diets on the part of hospital personnel would be eliminated as well as reducing chances of contamination. Heretofore, commercialization of a ready-to-use form has not been practical due to the inherent lack of stability in these diet formulations. Previous liquid diet compositions exhibit unacceptable levels of deterioration when subjected to the heat treatment required for effective sterilization, or even under the more ordinary conditions and ambiant temperatures associated with shelf life studies. As an example, Vivonex-HN.RTM. (Norwich Company, USA), the most popular of these elemental diets according to S. Ogoshi and H. Sato, Japanese Journal of Surgery, Vol. 11, No. 5, pages 391-397 (1981), states on its label that when mixed with water, Vivonex or High Nitrogen Vivonex may be left at room temperature for up to 8 hours or refrigerated for up to 24 hours. Previous label directions cautioned "In normal dilution, the solution is a perishable liquid food, and refrigeration is necessary. No more than the amount for a single day should be prepared at a time."
A major objective, therefore, of the present invention was to provide a liquid diet formulation in ready-to-use form which possessed adequate stability compared with previous diet formulations so that physical and nutritional quality would not be lost during sterilization and extended storage.
Aside from bacterial contamination there appear to be two other major underlying causes responsible for physical and nutritional deterioration of prior liquid diet compositions. One type of deterioration, primarily physical, can result from emulsion breakdown of the liquid composition which results in the oiling out of the lipid phase, or from precipitation of a solid, usually a mineral compound. Since elemental diets are frequently administered by enteral tube feeding via nasogastric tubing, physical stability of the liquid as a single phase is a critical prerequisite. P. L. LaMar, et al., Journal of Food Science, Vol. 44, pages 1168-1171 (1976) recognized the problem of emulsion breakdown in stability studies of liquid diets. The data indicated that diet emulsions made either from low heat-treated fish protein or from peptides derived from fish proteins, were more stable than those emulsions prepared with purified amino acids. High amylose starch also had a greater stabilizing effect on the emulsions than normal or waxy starch. Emcol AA-45 (a mixture of diacetyl tartaric acid esters of mono- and diglycerides manufactured by Witco Chemical Company, Los Angeles, Calif.) was used as an emulsifier in these studies. This work of LaMar et al relates to the present invention in that a similar mixture of diacetyl tartaric acid esters of mono- and diglycerides is also employed as one of the emulsifying agents in the instant diet.
A second type of deterioration besetting prior formulations of liquid elemental diets is due to the well known chemical reaction (i.e. browning) between amino acid moiety amine groups and carbohydrate carbonyl groups or their equivalent. For this reason ready-to-use liquid elemental diets have not been practical previously because they could not withstand the rigors of processing or maintain stability during the periods of storage required for such manufactured items. When the carbohydrate component and the protein source of such prior diets are put into solution, chemical reactions begin which result in the formation of condensation products which accumulate on standing, adversely affecting color, taste, and reducing the nutritional potential of the carbohydrate and protein ingredients. This process is further accelerated by increased temperature. An integral part of processing of any ready-to-use nutritionals is sterilization to eliminate spoilage caused by bacterial contamination. The instant diet composition is stable under sterilization conditions (above 212.degree. F. for approximately 10 minutes) whereas the '554 Winitz patent cautioned against conditions other than those (either no more than 1 minute at 194.degree. F. (90.degree. C.) or no more than 5 minutes at 140.degree. F. (60.degree. C.)) consistent with mild pasteurization. The nature of the instant diet composition allowing sterilization and its processing will be disclosed more fully hereinafter.
A second objective of the present invention was to provide a ready-to-use liquid diet composition having a high nitrogen content with improved nutritional performance. A critical parameter for clinically assessing nutritional support is nitrogen balance. To improve nutritional performance in a diet composition, experimental work leading to the present invention has indicated the importance of the protein source being rich in branched amino acids, as well as selection of specific mineral salts found to be compatible with processing conditions. The subject diet composition also contains a significant amount of the protein equivalent in the form of small peptides.
Protein quality, somewhat difficult to assess, is a major determinant of nutritional performance in these diets. Measured in nutritional studies, retention of dietary nitrogen by a patient being fed a liquid diet is a key indicator of the diet's protein quality. A controlled trial comparing the composition of the instant invention with Vivonex-HN as reported by C. Arteaga, et al in Clinical Research, Vol. 29, No. 5, page 818A (December 1981) and by J. Smith, et al., in J. Parenteral Enteral Nutr., Vol. 5, No. 6, page 559 (1981); and in The New England Journal of Medicine, Vol. 306, No. 17, pages 1013-1018 (1982); demonstrated that the instant diet composition was statistically significantly superior to Vivonex-HN in nitrogen utilization as measured by higher retention of absorbed nitrogen and lower azotemia.
In summary, the liquid diet composition of the present invention represents the first elemental diet which can be formulated and processed (i.e. sterilized) to yield a stable liquid, ready-to-use form which is equal or superior to reconstituted diet formulations with respect to physical stability and nutritional utilization.